The present invention relates generally to organometallic catalysts, and more specifically to the catalytic conversion of a racemic mixture of dienes to a cyclic olefin by a ring-closing metathesis (RCM) reaction. The present invention also provides a method for converting achiral or meso substrates into at least one enantiomer of a product through reactions referred to as a catalytic, enantioselective desymmetrization reactions.
The formation of carbonxe2x80x94carbon bonds remains among the most important reactions in synthetic organic chemistry. Consequently, the development of transition metal catalyzed carbonxe2x80x94carbon bond formation represented a significant advance in organic synthesis. One reaction involving transition metal catalyzed carbonxe2x80x94carbon formation is olefin metathesis. Olefin metathesis can be defined conceptually as a mutual exchange of alkylidene units between two olefins involving both the formation and cleavage of carbonxe2x80x94carbon double bonds. Transition metal ion catalysts allow this reaction to proceed in a facile manner through a [2+2] cycloaddition between an Mxe2x95x90C center and a carbonxe2x80x94carbon double bond. When two olefin groups are located on the same molecule and are subjected to olefin metathesis conditions, a ring-closing metathesis (RCM) reaction can occur in which a series of olefin metathesis reactions produce a cyclic olefin. Ring-closing metathesis is most facile for 5-7 membered ring systems because of the low ring strain afforded by these compounds. Ruthenium and molybdenum alkylidene complexes have proven capable of ring closing dienes having a variety of functional groups.
RCM reactions are generally plagued by undesirable reactions that compete with ring formation, such as acyclic diene metathesis and ring opening metathesis. The former reaction involves polymer formation through the metathesis of terminal dienes whereas the latter reaction comprises metathesis reactions of the ring-closed cyclic olefin. These competing reactions can be circumvented, for example, by performing the reactions under dilute conditions, optimizing ring sizes and utilizing hindered olefin substrates. The latter strategy is also useful for directing the initial reaction of the metal alkylidene towards one olefinic site in a diene over the other olefinic group.
The development of asymmetric ring closing metathesis has considerable potential as a powerful synthetic tool for the preparation of ring structures of defined stereosymmetry. For example, a logical application of asymmetric RCM is the synthesis of natural products which contain varying sizes of ring systems having pendant functional groups of specific stereosymmetry. U.S. Pat. No. 5,516,953 discloses a process for the preparation of optically active cycloolefins catalyzed by molybdenum and tungsten complexes. This process requires that substrate be initially isolated as an optically active diene. Olefin metathesis is catalyzed by molybdenum and tungsten halide or oxide complexes that may also contain alkoxide or amido ligands. In some instances, a tin, lead, aluminum, magnesium or zinc complex cocatalyst may be required.
U.S. Pat. No. 4,654,462 describes a process for olefin metathesis by a tungsten complex containing two phenoxy groups, a halogen atom, an alkyl radical and a carbene. Stereoselectivity is reported sufficient to control cis/trans isomerization in the metathesis of pure cis or trans olefins.
Only recently, the first report of an asymmetric RCM reaction involving the interaction of a chiral catalyst with a racemic substrate mixture was reported by Grubbs et al. J. Am. Chem. Soc. 1996, 118, 2499, Organometallics 1996, 15, 1865. A racemic diene substrate was added to a molybdenum alkylidene amido catalyst containing a dialkoxide ligand. At various conversion levels of the starting mixture, the enantiomeric excess of the unreacted diene mixture was analyzed, resulting in enantiomeric excess values of up to 48%. The enantiomeric excess of the ring-closed product was not reported. It was proposed that the dialkoxide had a rigid structure suitable to promote the transfer of asymmetry.
There remains a fundamental need for the synthesis of optically pure products by using asymmetric ring-closing metathesis reactions. In a recent review article, Blechert et al. discuss the state of the art relating to asymmetric RCM reactions, maintaining that xe2x80x9cIn light of the e.e. [enantiomeric excess] values obtained to date, synthetic applications of this process are currently not envisioned.xe2x80x9d Angew. Chem., Int. Ed. Engl. 1997, 36, 2036. Asymmetric processes only begin to show promise industrially when achieving enantiomeric excess values of at least 80%.
Another class of reactions that further advances the field of asymmetric synthesis is enantioselective desymmetrization reactions. The desymmetrization process involves converting achiral or meso substrates, i.e. substrates having a plane of symmetry, into a molecule having a stereocenter. If the desymmetrization reaction can be carried out enantioselectively, then one enantiomer is produced selectively in high enantiomeric excesses. In particular, desymmetrization reactions involving carbon-carbon bond formation have great potential in the pharmaceutical industry and in natural products synthesis, and only a limited number of examples have been reported in the literature. In Trost et al., palladium-catalyzed cyclization reactions yield chiral products having enantiomeric excesses of no more than 90%. Higher enantiomeric excess values can be obtained but only in the presence of added triethylamine. J. Org. Chem. 1998, 63, 1339-1341. In Mikami et al., carbonxe2x80x94carbon bond formation is effected between two substrates in an enantioselective fashion in the presence of a chiral titanium complex. J. Am. Chem. Soc. 1992, 114, 6566-6568. The field of asymmetric synthesis, however, remains wide open to increase the variety of desymmetrization reaction types and to improve synthetic conditions such as lower catalyst loadings, increased yields and conversions and decreased reaction times.
It remains a challenge to design a metal catalyst that can catalytically generate compounds having stereocenters while achieving high enantioselectivity.
In one illustrative embodiment of the present invention, a composition is provided having the structure: 
The composition has a chiral dialkoxide ligand, denoted by 
wherein the dialkoxide is of at least 80% optical purity. 
reaction site is of sufficient shape specificity, defined in part by the dialkoxide of sufficient rigidity and a Mxe2x95x90Nxe2x80x94R1 site to cause a mixture of two enantiomeric olefins to react with an Mxe2x95x90C center of the 
reaction site at different rates. The reaction is an olefin metathesis reaction and the product has at least a 50% enantiomeric excess of one enantiomer present in the original mixture. M is a metal ion, preferably molybdenum or tungsten.
In one embodiment of the invention, the group of atoms defining the shortest chemical bond pathway linking the oxygen atoms in 
contains at least four atoms. In another illustrative embodiment of the present invention, 
comprises the structure: 
The chiral dialkoxide transfers asymmetry to the composition such that the composition is at least 80% optically pure.
In another embodiment of the present invention, a method is provided wherein a diene mixture of enantiomers is reacted with the Mxe2x95x90C center of the above-mentioned composition. The method involves allowing a first enantiomer of the mixture to metathesize at M to an extent greater than a second enantiomer to form a product that has an enantiomeric excess of at least 50%. The metathesizing step occurs catalytically.
One aspect of the invention provides a method which includes a step of adding the racemic diene mixture to produce a ring-closed metathesis compound having an enantiomeric excess of at least 50% at 50% conversion of the diene mixture. Moreover, the enantiomeric excess of an enantiomer in the unreacted diene mixture is at least 50% at 50% conversion. The method allows 50% conversion of the racemic diene mixture to be achieved within a time of at least 5 minutes.
In another illustrative embodiment of the present invention, the diene comprises the structure: 
The diene contains one unsubstituted olefin group and one hindered olefin group to direct the initial metathesis towards the unsubstituted end. Reaction of the diene with the composition results in the formation of a ring-closed compound. The diene has a stereocenter and is available as a racemic mixture.
Another aspect of the invention provides a method for desymmetrization. The method involves the step of providing a molecular substrate having a plane of symmetry. A desymmetrization reaction is allowed to occur to form a product free of a plane of symmetry. In another aspect, the desymmetrization is allowed to occur in the absence of solvent.
Another aspect of the invention provides a method for catalytic desymmetrization. The method involves the step of providing a molecular substrate having a plane of symmetry and a catalyst. A desymmetrization reaction is allowed to occur to form a product having a quaternary carbon center in at least about 20% enantiomeric excess.
Another aspect of the invention provides a composition comprising a structure: 
M is a metal ion and 
is a chiral dialkoxide of at least 80% optical purity. The dialkoxide has sufficient rigidity such that a 
reaction site is of sufficient shape specificity, defined in part by the dialkoxide and a Mxe2x95x90Nxe2x80x94R site, to cause a molecular substrate having a plane of symmetry to react with a Mxe2x95x90C center at the 
reaction site. A catalytic olefin metathesis product is formed that has at least a 50% enantiomeric excess of at least one enantiomer present in the mixture. The product is free of a plane of symmetry.
Other advantages, novel features, and objects of the invention will become apparent from the following detailed description of the invention when considered in conjunction with the accompanying drawings, which are schematic and which are not intended to be drawn to scale. In the figures, each identical or nearly identical component that is illustrated in various figures is represented by a single numeral. For purposes of clarity, not every component is labeled in every figure, nor is every component of each embodiment of the invention shown where illustration is not necessary to allow those of ordinary skill in the art to understand the invention.